Alzheimer's disease is a progressive dementia that starts with decrease of short term memory and mild learning disability, develops higher brain dysfunction, particularly visuospatial agnosia, ideational apraxia, constructive apraxia and the like, and finally reaches movement disorder and so-called personality destruction, for which a method of radical treatment has not been found to date. There are predicted to be 2.4 million patients with Alzheimer's disease in the world in 2040, and the importance of a radical treatment method therefor or an early diagnosis thereof is increasing. The progression thereof is different from angiopathic dementia often found in Japan and is considered to continue over several years to ten years or more. In the case of a familial Alzheimer's disease caused by abnormal gene mutation, which is one of the Alzheimer's diseases, the condition of many of the patients rapidly worsens in several years, and the disease is characterized by an early onset since the age at onset is in their 30's-40's. Age, family history, genotype, hypertension, diabetes, smoking and the like are known as the risk factors of Alzheimer's disease other than the gene mutation, of which the relation with APOE genotype is clear. In particular, ApoE4 allele has already been reported as a risk factor of Alzheimer's disease (non-patent document 1).
As pathological changes characteristic in Alzheimer's disease, extracellular accumulation of amyloid plaque containing amyloid beta as a main constituent component, and accumulation of highly phosphorylated tau protein in nerve cells are widely known to occur. As for spatial and temporal pathological changes in brain, since accumulation of phosphorylated tau in the pyramidal cells in the hippocampus, particularly the region called CA1, is already observed in patients with early-onset Alzheimer's disease, the pyramidal cells in this region are considered to be spatially and temporally exposed to the strong influence of Alzheimer's disease in early stages, namely show fragility (non-patent document 2). On the other hand, since the movement disorder emerges almost at the final stage of Alzheimer's disease as mentioned above, the purkinje cell in the cerebellum is considered to be most resistant to Alzheimer's disease.
The incidence rate of Alzheimer's disease is considered to rapidly increase after 75 years old, and early detection and the start of an early treatment are important for suppressing the pathological progression by a symptomatic drug therapy.
Due to the absence of a radical cure for Alzheimer's disease at present, a diagnostic marker for early detection of Alzheimer's disease is energetically searched for, and the measurement of amyloid beta (Aβ40, Aβ42) and phosphorylated tau protein in blood or cerebrospinal fluid is considered to be the most promising. However, it is still difficult to clearly find acquisition of Alzheimer's disease in the future, that is, potential patients with Alzheimer's disease, even when these markers are used alone or in combination (for example, ratio of Aβ40 and Aβ42).